2′ and 3′-substituted cyclobutyl nucleoside analogs for the treatment of viral infections and abnormal cellular proliferation

Abstract

Provided are cyclobutyl nucleosides and methods for their use in treatment of infections including Retroviridae (including HIV), Hepadnaviridae (including HBV), or Flaviviridae (including BVDV and HCV) infection, or conditions related to abnormal cellular proliferation, in a host, including animals, and especially humans.

1. A cyclobutyl nucleoside of the formula (I)-(IV): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, salt of a prodrug, enantiomer, diastereomer, or tautomer thereof, wherein;
 Base is a purine or pyrimidine base; 
 Z is independently phosphate selected from the group consisting of monophosphate, diphosphate, triphosphate and a stabilized phosphate prodrug, P(O)Z′Z″, CH 2 P(O)Z′Z″, alkyl, sulfonate ester, or sulfonyl 
 Z′ and Z″ each independently is OH, OAlkyl, OAryl, alkyl, aryl, SH, SAlkyl, SAryl, NH 2 , mono or di-alkylamino, mono- or di-arylamino, or a residue of an amino acid; 
 A is O, S, or CH 2 ; or alternatively 
 A can be a covalent bond when Z is P(O)Z′Z″ or CH 2 P(O)Z′Z″; 
 R 1 , R 2 , and R 3  are independently hydrogen, lower alkyl, halogenated lower alkyl, CF 3 , 2-Br-ethyl, lower alkenyl, halogenated lower alkenyl, Br-vinyl, lower alkynyl, halogenated lower alkynyl, halo, cyano, azido, NO 2 , NH 2 , —NH(lower alkyl), NH(acyl), N(lower alkyl) 2 , —N(acyl) 2 , OZ, O(lower alkyl), O(alkenyl), C(O)O(alkyl), C(O)O(lower alkyl); or alternatively, 
 R 1  and R 2  together are ═CH 2  or ═CHY; or alternatively 
 R 1  and R 2  can come together to form a three-membered carbocyclic or heterocyclic ring, such as an epoxide ring; such that if R 1  is H, then R 2  is not CH 2 OH, and if R 2  is H, then R 1  is not CH 2 OH; 
 X is CH 2 , CHY, or S; and 
 Y is independently H, methyl, halogenated methyl, CF 3 , halogen, N 3 , cyano, or NO 2 . 
 
     
     
       2. The nucleoside of  claim 1 , wherein Z is phosphate selected from the group consisting of monophosphate, diphosphate, triphosphate and a stabilized phosphate prodrug. 
     
     
       3. The nucleoside of  claim 1 , wherein R 1  and R 2  are not both H. 
     
     
       4. The nucleoside of  claim 1 , wherein the base is a pyrimidine. 
     
     
       5. The nucleoside of  claim 4 , wherein the pyrimidine is a 5-fluorocytidine. 
     
     
       6. The nucleoside of  claim 1 , wherein the base is a purine. 
     
     
       7. The nucleoside of  claim 6 , wherein the purine is guanine or adenine. 
     
     
       8. The nucleoside of  claim 1 , wherein the nucleoside is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       9. The nucleoside of  claim 1 , wherein the nucleoside is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein each OH is replaced with OZ. 
     
     
       10. The nucleoside of  claim 9 , wherein the base is a pyrimidine. 
     
     
       11. The nucleoside of  claim 10 , wherein the pyrimidine is a 5-fluorocytidine. 
     
     
       12. The nucleoside of  claim 9 , wherein the base is a purine. 
     
     
       13. The nucleoside of  claim 12 , wherein the purine is guanine or adenine. 
     
     
       14. The nucleoside of  claim 9 , wherein Z is phosphate selected from the group consisting of monophosphate, diphosphate, triphosphate and a stabilized phosphate prodrug. 
     
     
       15. The nucleoside of  claim 1 , wherein the nucleoside is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein each OH is replaced with OZ. 
     
     
       16. The nucleoside of  claim 15 , wherein the base is a pyrimidine. 
     
     
       17. The nucleoside of  claim 16 , wherein the pyrimidine is a 5-fluorocytidine. 
     
     
       18. The nucleoside of  claim 15 , wherein the base is purine. 
     
     
       19. The nucleoside of  claim 18 , wherein the purine is guanine or adenine. 
     
     
       20. The nucleoside of  claim 1 , wherein the nucleoside is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein each OH is replaced with OZ. 
     
     
       21. The nucleoside of  claim 20 , wherein the pyrimidine. 
     
     
       22. The nucleoside of  claim 21 , wherein the pyrimidine is a 5-fluorocytidine. 
     
     
       23. The nucleoside of  claim 20 , wherein the base is a purine. 
     
     
       24. The nucleoside of  claim 23 , wherein the purine is guanine or adenine. 
     
     
       25. The nucleoside of  claim 1 , wherein the nucleoside is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, salt of a prodrug, enantiomer, diastereomer, or tautomer thereof. 
     
     
       26. The nucleoside of  claim 25 , wherein the base is a pyrimidine. 
     
     
       27. The nucleoside of  claim 26 , wherein the pyrimidine is a 5-fluorocytidine. 
     
     
       28. The nucleoside of  claim 25 , wherein the base is a purine. 
     
     
       29. The nucleoside of  claim 28 , wherein the purine is guanine or adenine. 
     
     
       30. The nucleoside of  claim 1 , wherein the nucleoside has an effective concentration to achieve 50% viral inhibition (EC50) when tested in an appropriate cell-based assay, of less than 15 micromolar. 
     
     
       31. The nucleoside of  claim 30 , wherein the nucleoside is enantiomerically enriched. 
     
     
       32. A pharmaceutical composition comprising an effective amount of the nucleoside of  claim 1 , or a pharmaceutically acceptable salt or prodrug thereof together with a pharmaceutically acceptable carrier or diluent. 
     
     
       33. A pharmaceutical composition comprising an effective amount of the nucleoside of  claim 1 , or a pharmaceutically acceptable salt or prodrug thereof together with a pharmaceutically acceptable carrier or diluent and in combination with one or more other antiviral agents. 
     
     
       34. A method of treating an HIV infection in a mammal comprising:
 administering to a mammal in need thereof an effective amount of a nucleoside of  claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier or diluent. 
 
     
     
       35. A method of  claim 34 , wherein Z is a phosphate selected from the group consisting of monophosphate. diphosphate. triphosphate and a stabilized phosphate prodru. 
     
     
       36. A method of  claim 34 , wherein the mammal is a human. 
     
     
       37. A compound of  claim 2 , wherein Z is triphosphate. 
     
     
       38. A pharmaceutical composition of  claims 32  or  33 , wherein Z is triphosphate. 
     
     
       39. A method of  claims 35  or  36 , wherein Z is triphosphate.